Heparin catalyses, in particular via antithrombin III (AT III), the inhibition of two enzymes which are involved in the blood coagulation cascade, namely factor Xa and factor IIa (or thrombin). Preparations comprising low molecular weight heparins (LMWHs) comprise chains formed of 4 to 30 monosaccharides and have the property of acting more selectively with respect to factor Xa than with respect to thrombin.
It is known that the inhibition of factor Xa requires attachment of heparin to AT III via the antithrombin-binding domain (Domain-A) and that inhibition of factor IIa (thrombin) requires attachment to AT III, via the Domain-A, and to thrombin via a less well defined binding domain (Domain-T).
Synthetic oligosaccharides corresponding to the Domain-A domain of heparin are known. They are disclosed, for example, in Patents EP 84 999 and EP 529 715, the patent application published under the number WO 99/36428 and the publication Bioorg. Med. Chem., 1998, 6, 1509-1516. These synthetic oligosaccharides have the property of selectively inhibiting, via antithrombin III, factor Xa of the coagulation without any activity with respect to thrombin. They display an antithrombotic activity in venous thrombosis.
Synthetic oligosaccharides capable of inhibiting thrombin and factor Xa via activation of AT III have been disclosed in the patent applications published under the numbers WO 98/03554 and WO 99/36443.
Novel biologically active sulphated and alkylated polysaccharide derivatives are disclosed in these patent applications. They are in particular anticoagulants and antithrombotics. It has in particular been shown that these sulphated and alkylated polysaccharides can be powerful antithrombotics and anticoagulants depending upon the arrangement of the alkyl groups and sulphate groups carried by the glucide backbone. More generally, it has been found that, by preparing polysaccharide sequences, it is possible to precisely adjust the activities of GAGs type in order to obtain very active products exhibiting the anticoagulant and antithrombotic pharmacological properties of heparin. In comparison with heparin, they exhibit the advantage of having a specific structure and of not reacting with platelet factor 4, the cause of the thrombocytopenic effects of heparin.
However, the use in human therapeutics of some products disclosed in the patent applications published under the numbers WO 98/03554 and WO 99/36443 and in Patent EP 529 715 can prove to be problematic, in particular if these products have a long half-life. In the field of the prevention or treatment of thrombosis with the above products, the fluidity of the blood has to be reestablished or maintained while preventing a haemorrhage from being brought about.
This is because it is well known that a haemorrhage can be triggered in a patient under treatment by any accidental cause. It may also be necessary to intervene surgically in a patient under antithrombotic treatment. Furthermore, during some surgical procedures, anticoagulants may be used at a high dose so as to prevent blood coagulation and it is necessary to neutralize them at the end of the operation. It is therefore advantageous to have antithrombotic agents which can be neutralized in order to stop the anticoagulant activity at any time. In point of fact, the known synthetic oligosaccharides described above cannot be easily neutralized by the known antidotes for heparin or LMWHs, including protamine sulphate.